Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer.

PURPOSE: Panitumumab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status. PATIENTS AND METHODS: Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status. RESULTS: From June 2006 to March 2008, 1,186 patients were randomly assigned 1:1 and received treatment. KRAS status was available for 91% of patients: 597 (55%) with wild-type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio [HR] = 0.73; 95% CI, 0.59 to 0.90; P = .004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR = 0.85, 95% CI, 0.70 to 1.04; P = .12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse event rates were generally comparable across arms with the exception of known toxicities associated with anti-EGFR therapy. CONCLUSION: Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.

A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens.

INTRODUCTION: AZD6244 (ARRY-142886) is a potent, selective MEK inhibitor. This study aimed to evaluate the efficacy and safety of AZD6244 versus pemetrexed as second- or third-line treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: In this randomized phase II study, patients received either 100 mg oral AZD6244 free-base suspension twice daily or 500 mg/m(2) intravenous pemetrexed once every 3 weeks after pretreatment with a corticosteroid, folic acid, and vitamin B12. The primary end point of the study was the disease progression event count. RESULTS: Eighty-four patients were randomized. Disease progression events were experienced by 28 (70%) and 26 (59%) patients in the AZD6244 and pemetrexed groups, respectively. Median progression-free survival was not statistically significantly different between the AZD6244 and pemetrexed groups (67 versus 90 days, respectively; hazard ratio 1.08, two-sided 80% confidence interval = 0.75-1.54; p = 0.79). Two patients in the AZD6244 group had a best response to treatment of partial response. In the pemetrexed group, one patient achieved a complete response and one patient a partial response. Dermatitis acneiform, diarrhea, nausea, and vomiting were the most frequently reported adverse events with AZD6244, compared with fatigue, anemia, nausea, anorexia, and dermatitis acneiform with pemetrexed. CONCLUSIONS: Oral AZD6244 showed clinical activity as second- or third-line therapy for patients with advanced NSCLC. In an unselected NSCLC population, there is no suggestion that AZD6244 monotherapy offers any advantage over standard treatment with pemetrexed. Based on preclinical data and recent clinical observations, further development of AZD6244 in NSCLC should focus on BRAF or RAS mutation-positive patients and/or AZD6244-based combination regimens.

Therapy of small cell lung cancer with emphasis on oral topotecan.

Systemic chemotherapy plays the major role in the management of patients with small cell lung cancer. Cisplatin plus etoposide is the most widely used regimen and is considered as standard in patients with limited disease. Cisplatin plus irinotecan improved survival compared to cisplatin plus etoposide in a Japanese trial but failed to do so in two trials in Caucasians. Cisplatin plus topotecan had similar efficacy compared to cisplatin plus etoposide in patients with extensive disease. In the second-line setting, topotecan showed similar efficacy but better tolerability compared to cyclophosphamide, doxorubin plus vincristine. Oral topotecan was as efficacious as its intravenous formulation and was shown to improve survival compared to best supportive care alone in patients previously treated with chemotherapy. Thus topotecan is considered as the standard second-line chemotherapy in patients with small cell lung cancer.

Current standards in the treatment of metastatic breast cancer with focus on Lapatinib: a review by a Central European Consensus Panel.

In breast cancer, early detection as well as new developments in therapeutic options has resulted in less patients presenting with metastatic disease. However, about one-third of women with early stage breast cancer will eventually develop metastatic disease. Furthermore, approximately 20-30% of patients with breast cancer have tumors that overexpress human epidermal growth factor receptor (HER-2), which is associated with an aggressive tumor phenotype and poor prognosis. The identification of the HER-2 protein led to the development of highly effective therapeutics directed at this receptor. Trastuzumab, a recombinant, humanized, monoclonal antibody that binds to the extracellular domain of the HER-2 protein, has shown significant clinical benefit in metastatic and early-stage HER-2-positive breast cancer. Since the cancer recurs after adjuvant therapy in some women, and metastatic breast cancer eventually develops resistance to trastuzumab, there is a need for alternative treatment modalities to block HER-2 signaling. One of these treatment options is lapatinib, an orally active small molecule that inhibits the tyrosine kinases of HER-2 and the epidermal growth factor receptor type 1 (EGFR). In this consensus statement current treatment options in metastatic and locally advanced disease are discussed with a special focus on lapatinib.

Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine in anthracycline-pretreated metastatic or locally recurrent inoperable breast cancer patients: a prospective multicentre trial of the Central European Cooperative Oncology Group (CECOG).

Docetaxel (D) plus gemcitabine (G) is an active combination in anthracycline pre-treated breast cancer. Impact of sequential administration of these drugs is unclear. This trial aimed to compare concomitant DG with sequential D --> G. Patients were randomised to eight cycles of gemcitabine 1,000 mg/m2 on days 1 + 8 plus docetaxel 75 mg/m2 on day 8, or 4 cycles of docetaxel 100 mg/m2 on day 1, followed by four cycles of gemcitabine 1,250 mg/m2 on days 1 + 8, in a 21-day schedule. Time to progression (TTP) was defined as primary endpoint; secondary endpoints were overall response rate (ORR), response duration (RD), overall survival (OS) and toxicity. Due to poor recruitment, the trial was terminated after 100 of a pre-planned 430 patients. Patient characteristics were well balanced. No significant difference was observed in terms of TTP, ORR, RD and OS. Grade 3/4 adverse events encompassed leucopoenia (29 vs.68%, P < 0.001), neutropoenia (49 vs. 83%, P < 0.001) and febrile neutropoenia (4 vs. 9%, n.s.), all favouring D --> G. No difference in efficacy was observed between concomitant and sequential treatment. D --> G produced significantly more episodes of haematological toxicity due to the administration of docetaxel at 100 mg/m2 without GCSF support.

Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.

BACKGROUND: Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. METHODS: This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m(2), day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B(12), folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. FINDINGS: All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4.3 months [95% CI 4.1-4.7] vs 2.6 months [1.7-2.8]; hazard ratio [HR] 0.50, 95% CI 0.42-0.61, p<0.0001) and overall survival (13.4 months [11.9-15.9] vs 10.6 months [8.7-12.0]; HR 0.79, 0.65-0.95, p=0.012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0.0001), specifically fatigue (22 [5%] vs one [1%], p=0.001) and neutropenia (13 [3%] vs 0, p=0.006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0.0001). INTERPRETATION: Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. FUNDING: Eli Lilly.

Therapeutic effects of epoetin zeta in the treatment of chemotherapy-induced anaemia.

OBJECTIVE: To perform an open, non-controlled, multiple-dose, international, multicentre, phase III study to evaluate epoetin zeta, a biosimilar epoetin referenced to epoetin alfa, for the treatment of chemotherapy-induced anaemia in patients with cancer. METHODS: Safety, tolerability and efficacy of subcutaneously administered epoetin zeta were assessed in 216 patients with solid tumours or non-myeloid haematological malignancies receiving chemotherapy and at risk of transfusion. RESULTS: A significant (p < 0.0001) increase in mean haemoglobin (Hb) level (1.8 g/dL) was observed between baseline and week 12 (intent-to-treat population); 176/216 (81.5%) patients achieved a response (increase in Hb > or = 1 g/dL or reticulocyte count > or = 40,000 cells/microL) by week 8. Over the treatment period, 231 treatment-emergent adverse events were experienced by 91 patients; 9/216 (4.2%) experienced a clinically significant thrombotic event within the first 12 weeks of epoetin zeta treatment, significantly lower than the assumed 18% baseline incidence (p < 0.0001) based on historical data from epoetin trials. No transfusion was necessary for 175/216 patients (81.0%) and quality of life improved over the study. No patients developed anti-erythropoietin antibodies. Sponsor trial no: CT-830-05-0009. CONCLUSION: This study demonstrates that subcutaneously administered epoetin zeta is well-tolerated and has efficacy in the treatment of anaemia in patients with cancer receiving chemotherapy and at risk of transfusion.

Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer.

PURPOSE: This open-label, randomized, multicenter phase III study compared oral topotecan/intravenous cisplatin (TC) with intravenous (IV) etoposide/cisplatin (PE) in patients with untreated extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: A total of 784 patients were randomly assigned to either oral topotecan 1.7 mg/m2/d x 5 with IV cisplatin 60 mg/m2 on day 5 (n = 389) or IV etoposide 100 mg/m2/d x 3 with IV cisplatin 80 mg/m2 on day 1 (n = 395) every 21 days. RESULTS: Overall survival (primary end point) was similar between groups (P = .48; median: TC, 39.3 weeks v PE, 40.3 weeks). One-year survival was 31% (95% CI, 27% to 36%) in both groups and the difference of -0.03 (95% CI, -6.53 to 6.47) met the predefined criteria of < or = 10% absolute difference for noninferiority of TC relative to PE. Response rates were similar between groups (TC, 63% v PE, 69%). Time to progression was slightly but statistically longer with PE (log-rank P = .02; median: TC, 24.1 weeks v PE, 25.1 weeks). The regimens were similarly tolerable. Grade 3/4 neutropenia occurred more frequently with PE (84% v 59%), whereas grade 3/4 anemia and thrombocytopenia occurred more frequently with TC (38% v 21% and 38% v 23%, respectively). Lung Cancer Symptom Scale scores were statistically better with PE, but the differences were small and of debatable clinical significance. CONCLUSION: Oral topotecan with cisplatin provides similar efficacy and tolerability to the standard (etoposide with cisplatin) in untreated ED-SCLC and may provide greater patient convenience compared with intravenous etoposide and cisplatin.

Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial.

PURPOSE: The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. PATIENTS AND METHODS: Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). RESULTS: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p = 0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. CONCLUSION: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.

Gemcitabine, epirubicin, and paclitaxel versus fluorouracil, epirubicin, and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: a Central European Cooperative Oncology Group International, multicenter, prospective, randomized phase III trial.

BACKGROUND: The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles. RESULTS: Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm. CONCLUSION: No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.